Inhibition of Brain Type A Monoamine Oxidase and 5‐Hydroxytryptamine Uptake by Two Amphetamine Metabolites, p ‐Hydroxyamphetamine and p ‐Hydroxynorephedrine

Two amphetamine metabolites, p ‐hydroxyam‐phetamine ( p ‐OHA) and p ‐hydroxynorephedrine ( p ‐OHN), selectively inhibited the A form of monoamine oxidase (MAO) in rat and mouse forebrain homogenates. Of these two metabolites, p ‐OHA inhibited MAO‐A more strongly than p ‐OHN. This MAO‐A‐selective inhibition by p ‐OHA or p ‐OHN was found to be competitive with respect to deamination of its substrate, 5‐hydroxytryptamine (5‐HT). The degree of MAO‐A inhibition was not changed by 90 min of preincubation of the enzyme preparations with either metabolite, and the activity inhibited by p ‐OHA after the preincubation recovered completely to the control level after repeated washing. Uptake of 5‐HT or dopamine into mouse forebrain synaptosomes was highly reduced by both p ‐OHA and p‐ OHN. Both metabolites were more potent in reducing dopamine uptake than in reducing 5‐HT uptake. In reduction of 5‐HT and of dopamine uptake, p ‐OHA was more potent than p ‐OHN. These results indicate that p ‐OHA is a more selective inhibitor of brain MAO‐A activity and 5‐HT uptake than its subsequent metabolite, p ‐OHN. These two actions of p ‐OHA might, together with possible 5‐HT efflux into the synaptic cleft, greatly contribute to head twitch, a brain 5‐HT‐mediated animal behavior induced by p ‐OHA.